Fleming's seminal 1929 article on penicillin is missing two words : impurities and crude

Fleming, in this extremely famous article, defines his "penicillin" as consisting of  one or more soluble solid active ingredients in a liquid nutritional  broth, no more and no less.

He makes it clear that "penicillin" is merely a useful shorthand for that cumbersome longer phrase.

He never once uses the word impurities or impure or crude: to him his active ingredient is perhaps ALL  of the soluble solids left behind when the water is evaporated .

Fleming says that this (mixture) of soluble solids and nutritional broth is non-toxic to the extent that it can be injected in a mass of one fortieth of body weight without harm.

(That is, this liquid mixture appears to be safely injectable in a mouse and a rabbit to the equivalent of  a single bolus of 1500 to 2000 cc into an average adult human.)

And Fleming isn't the only one never to use impurities or crude in describing penicillin in a scientific report, in the twelve years between 1928 and 1940.

Clutterbuck & Raistrick in 1932 do not use the words impurities or crude, nor does Roger Reid in 1934, or Elizabeth Pickering at Squibb in 1937 or Siegbert Bornstein in 1939.

But Howard Florey, the chemist manque , the anti-clinician, he sure does in 1940.

He might even ask his potential readers, "Purity : how many ways do you want it ?"

Despite being a very short article - almost more of a scientific note  in the style of letters to the journal Nature - Florey manages to inject the words "purify" , "not a pure substance", "impure" and "impurities" and talks constantly of his "penicillin preparations" as if they are something quite different and advanced from Fleming's liquid penicillin.

But, in fact, Florey has merely concentrated all the soluble solids by evaporating away the water, so that 4 tiny units of anti-bacterial activity are no longer in a gram of water and solubles, but in a milligram of solubles.

But two thirds of the scarce anti-bacterial activity has been lost in this totally unnecessary and expensive and complex effort : and in any case, this dry powder has to have water added back into it, to inject it for use !

Dawson, Pulvertaft, Duhig, Yermolieva , Berger (among a mere handful of all the world's doctors ---- maybe just .01% of them  thought this way) seemed to have picked up on Fleming's crucial point.

A point he quickly missed, because he publicly always said that the substance would have to be synthesized pure by chemists before it might be a useful antiseptic .

But his original point was true, nevertheless.

It was this : that regardless of whatever was the compound(s) with that mixture of soluble solids that had the anti-bacterial powers, the water and other solids had no harmful effect and needn't be laboriously purified out - or even concentrated by evaporation - at a tremendous loss of the anti-bacterial matter.

Dawson is at pains to introduce the word "crude" repeatedly in his 1941 article, but with a much different point that Florey's article a few months earlier.

Dawson wants to hammer home that despite the crudity of this mixture of the anti-bacterial activity and the other soluble solids, it was still non-toxic even when injected ( finally) into the human blood stream : life-saving does not have to wait until the chemist's apple has been polished to a 't' .

Dawson is , in a sense , "The James Lind of Penicillin".

Put in another way, James Lind said we don't know which compound (later determined to be vitamin c) it is in limes that prevents scurvy but that shouldn't stop us from using it - NOW ! - to save lives.

Almost two hundred years later, another Scottish (Canadian) doctor (Henry Dawson) said pretty much the same thing.

The lesson might be this : chemists, let the sleeping dogs of chemical perfection lie -----  while we clinicians get on with saving lives.....

Wartime penicillin's biggest secret was "hidden in plain sight", on the pages of the very first article on penicillin

The real reason why the tortoise Henry Dawson, despite starting almost three years late, beat the hare Howard Florey to become the first ever to put an injection of an antibiotic into a human patient, is to be found inside wartime penicillin's biggest secret.

Unexpectedly, wartime penicillin's biggest secret was not stamped "TOP SECRET" and was not buried under lock and key in some government cabinet in Washington or London.

Instead, Henry Dawson discovered it in October 1940, incredibly enough "hidden in plain sight" , on the pages of Alexander Fleming's very first article on penicillin from back in 1929.

Hidden from even its own author for all those years ; remaining hidden to almost everyone ever since - except for a very few caring and observant wartime doctors.

The great secret is all about non-toxicity and natural penicillin.

No, no , no, ---- don't jump the gun.

Its not that penicillin is non-toxic (because in some crucial ways it is not).

Rather more surprising, the great secret turns on the lucky fact that natural penicillin's natural impurities are so relatively non-toxic.

Fungus are very much a mixed bag on the toxicity front. Lots of them are so non-toxic that we love to eat them as our daily food : bread, beer, cheese, mushrooms, tofu and treated milk products.

Others release tiny amounts of toxins (mycotoxins) so toxic they rate up there with the most deadly poisons we know, by weight.

Back to 1928.

After about ten days of activity, and after a good straining through a lab filter to remove all solids, a gram of Fleming's 1928 penicillium liquid medium contained one part per million of penicillin -- one microgram of penicillin , ie about 1.6 units of bacteria killing activity .

97% of that gram was pure water and the remaining 3% were natural impurities - mostly organic acids.

We humans eat organic acids all the time - particularly in preference to their alkaline opposites, the bases.

Unfortunately, in a the world obsessed with eugenic purity, the good news ended with this particular penicillium strain's thankful lack of general toxicity.

The Age of Modernity liked things to be distinct and separate, not buried together in mixtures : it demanded purity in everything, from the German race to the Allied brand of penicillin.

Unfortunately for this obsession with purity, those various natural acids produced by the penicillium were so much like penicillin chemically (though not at all in anti-bacterial activity) that they were almost impossible to separate from penicillin without either destroying it and or losing it along the way.

In September 1940, at the start of their teaching hospital's first term, Henry Dawson had agreed to restrain his instinct to try and save lives.

Restrain himself, until his fellow team member, chemist Karl Meyer, had purified their penicillin (that the tiny team was home- growing) to a point where it was judged 'pure' enough to inject safely in a human body.

The projected launch date was the start of next school term, in early January 1941: ironically the exact same time Howard Florey's team was scheduled to start injecting their 'purified' penicillin into humans ! Dawson's team didn't know this, how close they came to be 'also-rans' .

Florey thought his team so far ahead he felt no particular urgency to rush into saving lives ; purity and not humanity, was always more his 'thing' anyway.

But ultimately Dawson couldn't stand to stand idly by as two young boys died needlessly from the dreaded and invariably fatal SBE (subacute bacterial endocarditis).

Not when he was convinced that penicillin's unique combination of non-toxicity, potency and diffusibility  could save them.

He had not much literature on penicillin to read and re-read while waiting for the difficult process of purification to succeed , not in October 1940: only five articles .

Suddenly he realized that there was a possible solution to his moral dilemma , in that literature and right there under his nose all the time.

 All five authors, beginning with Fleming, had mentioned that natural penicillin's natural impurities were not really toxic - at worse, a minor irritant.

So why continue to purify and purify penicillin - at an enormous cost in labour and in penicillin losses?

Why labour to purify it past the point where it could be concentrated (like orange juice),  just enough to have a useful therapeutic effect without literally drowning the body in excess water ?

At that time, Dawson team was often making penicillin brew so weak that pouring it directly into a human body (by IV drip) would require putting a kilo of water into the blood stream for every 1000 units of penicillin activity !

But one go around of initial concentration cum purification might result in a little dirty brown powder that assayed 8 units per mg (one thousands of a gram) - 50 mgs of this powder dissolved in a gram of a suitable liquid, 3 times a day, would give the patient 1200 units of penicillin --- without the risk of drowning them internally.

And so on October 16th 1940, Henry Dawson jumped the gun and launched the Age of Antibiotics three months ahead of schedule.

Later on, by mid 1942, the raw penicillin juice made in hospitals assayed at around 40 units per ml of medium (about 25 times as pure) and it no longer needed to be even concentrated like orange juice (because even that resulted in heavy losses and needless additions of chemical contaminants).

It could simply be strained of solids, bottled and stored in a cold dark refrigerator until injected into a patient (and not merely dabbed into the patient's open wound, which was as far as most other penicillin pioneers were willing to go with non drug-company made penicillin.)

This is what a few brave penicillin pioneers (salute their heroic efforts please !) did : Robert Pulvertaft, James Duhig, and Zinaida Yermolieva.

Admittedly ,the first two did save lives by injecting raw penicillin into patients' blood supply, while still expressing some reluctance to do so  - by contrast, the soviet team led by Ms Yermolieva  did so routinely - all the more praise to them !

An unnecessary penicillin holocaust ...

If  only crude raw penicillin had been used to save lives, starting in 1928, millions of people would not have needlessly died world wide , in  a totally unnecessary holocaust bigger than anything Hitler had planned for the Jews .....

Wartime Penicillin was a race between a Tortoise and a Hare,unexpectedly the Tortoise won but the Hare got to phone-in the results...

People invariably find the story of wartime penicillin fascinating because 75 years after the earliest events, it still remains a real puzzler with lots of inexplicables and unanswered questions.

The story of wartime penicillin is actually quite clear.... but it is its history that seems so full of holes and silences.

A great Russian poet once voiced the thought that lovers only sing love songs when they are far apart --- when they are together they have much better things to do.

So too with the winners in the race  to define and provide wartime penicillin.

The selfless nature of the objectives of those who won the race suggests that they might be equally self-effacing in the moment of triumph : just glad that penicillin was being made available to all, at a reasonable price, and before the six year long war ended.

The losers in the penicillin race were grasping and ambitious and  lost so dramatically and so unexpectedly , and so it would seem natural for them to seek a form of physic revenge by re-writing the history of wartime history.

The losers were, in part, from the government side of the race and they had lots of taxpayers money to write and publish huge official histories.

Even after that, they held most of the solid documentation (which they thoughtfully marked as "secret" during the war) in their official archives.

The same governments that , after the war, offered to generously fund all academic researchers and research projects - that they approved of .

The losers were also Big Pharma , who held much of the unpleasant details in their closely guarded archives but who were willing to fund researchers and open their archives in a limited fashion to them, provided the drug executives had reason to feel the researchers were sympathetic to their view point.

And all the secondary researchers ever since have had to scramble from pillar to post to get any sort of firm information about the winning side of the race for penicillin , while information from the losers comes at them by the trainload in war friendly well light archives in Washington and London.

How balanced an account can we expect even the most dispassionate author to provide under those circumstances ?

My job , as I see it , is not to be dispassionate but rather a partisan for the winning side : but not to be a partisan for anybody on the winning side.

I will seek to establish a firm , fact-based chronology when things did happen (and more importantly, did not happen) and try to follow the money trail : ignoring talk and claims and promises for cold hard cash (and again : more importantly, lack of evidence of cold hard cash.)

I will review all contemporary claims of penicillin yields to judge if they were credible-- and few were.

Above all, I will separate clearly when the contemporary numbers refer to absolute amounts and when they refer to relative amounts of penicillin : for this is one of the widest failings in all accounts about penicillin and one that is at the very core of the muddle about wartime penicillin.

The winning side wanted larger and larger absolute amounts of penicillin --- to help those dying of infection, in all countries, as soon as possible.

The relative purity of those absolute units of therapeutic penicillin interested them not in the slightest : greater and greater production of absolute units of therapeutic penicillin was their only concern.

Four daily injections of 500 cc of crude penicillin juice , with about 2 units of penicillin per filtered ml of medium, (4000 units of absolute penicillin per day , in total) was judged useful to Australian Jimmy Duhig because it saves a mother's live , even though that material (in relative terms of purity) was only 1 part per million of the medium !

 By way of pointed contrast, his fellow Australian Howard Florey was very proud in getting a single milligram of solid penicillin from the same amount and strength of penicillin juice, because it assayed at 450 units per mg, ie 25% pure.

Duhig's yield of therapeutic penicillin was 100% because he lost nothing trying to purify it - and the impurities in his penicillin juice caused his patient no more than temporary discomfort.

Florey's yield was 12% , because his repeated attempts to purify his penicillin juice resulted in huge losses and huge destruction of the basic penicillin ---- and it introduced toxic chemical contaminants worse than the natural impurities it sought to get rid of !

A patient receiving this material as medicine would get much less penicillin and probably find it more painful to boot.

But thankfully , patients didn't usually get this sort of penicillin from Florey.

His patient-directed penicillin was only purified to about 40 units per mg, and while nominally 'dirtier' , was actually probably safer than the early 'pure' variety : and certainly the yield was much higher and so the patient got more absolute units of germ killing power.

(Bacteria are only killed by absolute amounts of penicillin not by its relative purity : after all, the greatest diluter of penicillin - by far - is not the original pint of medium fluid but rather the quarts of blood fluid in the human body !)

No, the "pure" (high relative purity) penicillin was a holy grail sought for only one reason : we need pure penicillin to determine its chemical nature for then Man can hope to artificially synthesize it and push Mother Nature out of the picture entirely.

Millions of patients died, needlessly, during the 15 plus years of this fruitless quest.

Wouldn't you also want to cover your tracks in this shameful episode of your life....

George Redmayne Murray : moral predecessor to Dawson,Duhig & Pulvertaft's penicillin efforts

moral predecessor to Henry Dawson

Dr George Redmayne Murray is no longer a name that trips off the lips of scientists and doctors, but he still has moral lessons to teach us today.


Thyroid conditions in his day, the 1890s, were started to being treated by grafting new thyroid glands from animals into the bodies of people with diseased ones.

It sort of worked - heroic medicine indeed.

This concept was more or less how Banting originally planned to cure diabetes.

But when Murray read of one such effort is Lisbon, he noted the results came far too immediately -  the same day in fact - for new blood vessels to have had time to grow for the organ to spread the juice of the gland into the body.

The juice must have diffused outward from the new organ, on its own.

In which case, the juice alone, from ground-up animal organs, might work - without the need for an expensive and dangerous major operation to insert the organ itself.

(And let us not go into rejection problems !)

And here is where the application to chivalrous penicillin came in : he immediately extracted the juice of animal thyroid, added a little of a bog-common preservative to the juice to kill off any bacteria within, and injected it cautiously, just under the skin, into a patient with thyroid disease.

It worked -- she recovered her strength- and the first ever successful hormone deficiency treatment had happened for the price of a hot dinner, and in about the same time period it takes to eat a hot dinner !

Insight and drive - not money - more often than not, really drives medical advances

Dawson, Duhig, Pulvertaft also injected their crude substance (penicillin juice) via this method : cautiously just under the skin ( the safest form of injection) and with a simple common preservative to kill any potential pathogens.

Advances in medicine don't always require armies of the ambitious (more eager to produce endless papers than to help patients) and factories full of equipment.

It sometimes just takes deep insight and a moral drive : Murray , like Dawson, clearly had both....

The Mystery of Penicillin's 18 missing years

I believe that all of the penicillin books up to now - and there have been hundreds of them - have basically been a series of 100,000 word excuses - "the dog ate my penicillin homework".

Excuses to us - the lay public - on behalf of Science in general or on behalf of one or other early penicillin researchers in particular.

But eighty years later, we lay people still want to know why it was that the best life saving medicine this world will ever see took an eighteen year vacation (from September 1928 till about September 1946) before local doctors around the world could routinely prescribe it to save a life.

Whether they are from the pen of a medical historian  seeking to defend all of Science/a particular team effort or the effort of a lay author defending an individual scientist they particularly admire, all those apologies basically come down to this:

The 18 year delay was due to technical difficulties, not moral failings - at least not the moral failings of my hero.

My book, by contrast, is not going to be a technical book - at least in its intentions.

(It will actually highly technical and highly accurate at times---- but only when needed to refute technical excuses and bromides.)

THE FIRST MORAL HISTORY OF PENICILLIN

Mine will be a Moral History of penicillin - it will lay out a thesis that it was moral failings, not technical difficulties, that delayed penicillin becoming popularly know and commonly prescribed during all those years of death and suffering that we now call The Great Depression and World War Two.

The two events caused an excess of 100 million premature deaths over what might have been expected in that 16 year period.

Even if we content to 'merely' reduce those excessive deaths and not seek to prevent many of the so-called normal infectious deaths, how millions might penicillin have saved if it was readily available by 1929-1930?

Or consider this: despite the new global threat from nuclear weapons, the Cold War period from 1945 till 1985 was actually an incredibly optimist period in world human history.

The promise of 1945's penicillin was sufficient, all by itself, to overcome the fear induced by 1945's A-Bomb.

For a generation, penicillin kept most of us buoyed up about ourselves and the world around us.

Could those good vibes - induced in 1928-1929 instead of twenty years later - have been enough, by themselves, to prevent the worst of the Great Depression and World War Two from even happening ?

We will never know.

 But I believe these questions are still big enough,eighty years on, for it to be worthwhile to re-examine the early penicillin saga to see if there is another explanation for the delay. One that will finally convince most lay people - and hopefully - even convince a few of the scientists.

DUHIG IS PROSECUTION'S KEY WITNESS 

In the Fall of 1943, in Brisbane Australia, 15 years after Fleming discovered penicillin, Dr J V Duhig saved the lives of a dozen seriously ill people using a form of penicillin juice no more sophisticated than what Fleming had on hand in November 1928.

This the single hard, hard, hard, hard ,hard, historical stone against which I am going to grind every author and every account that claims that there were 'technical complications' why the world had to wait 15 or more years to put the life-saving effects of penicillin to work.

Until and unless they can explain to everyone's satisfaction why Duhig could do this - but why Fleming/Florey and Dawson et all couldn't - I will not relent.....

VEGEMITE also had its hour ; one far fierce hour and sweet

Yellow Snow Bad; Yellow Uisce Beatha Good

It is no secret that Irishmen like their drink, even ( or perhaps, particularly) in wartime.

For a real Irishman likes nothing better than defying straitlaced authorites who think sugar and alcohol has higher uses in wartime than to just use in beverages - such as using them to make more and stronger explosive materials.

So in November 1943, it probably won't seem that unusual to see a feisty Irish-Australian named Jim Duhig sprinkle some yeast-like material over a vat of water and molasses and put it in a cool dark place for ten days.

We say yeast-like because yeast extract was unavailable in wartime Brisbane (Queensland) Australia.

Jim did what any quick thinking Aussie would do - he reached for that all purpose substitute, Vegemite in .3% solution, because after all, he did come from the land down under, where beer flows and strong men chunder.

Also not unusual was his decision to strain the resulting golden colored liquid at the bottom of the vat through a piece of cheesecloth and put it into bottles.

But what he did next might surprise you : he drew some of that golden liquor out in a big needle and stuck it - again and again - into a dying woman.

He saved her life with this golden uisce beatha and saved four other dying patients' lives with it as well, in addition to successfully treating another two dozen less severe infections with his brew.

Duhig's technique, as crude as it seems, is about as high tech as antibiotic science & industry ever has to get, if its only interest is in saving lives.

But it isn't and Jim Duhig's heroic actions came 15 years after Penicillin's initial discovery.

Millions would have lived ( longer - for we all must die at some time) if Alexander Fleming had felt in 1928 as Dr Duhig felt in 1943.

But he didn't and neither would have Dr Duhig in 1928.

It took someone else, someone far bolder than Fleming or Dunhig or Florey, to kickstart the radical-at-the-time idea that injecting natural penicillin into a patient's bloodstream was the best possible treatment of most life-threatening systemic bacterial infections.

That bold idea was first enacted upon on a tiny island, not far off the American coast, a few years earlier.....

Jim Duhig was indeed very Irish - his uncle was the archbishop of Queensland - but in real life he didn't brew liquor - or even drink - he was the head of a prohibitionist society.

But he did brew penicillin---- rather than see some patients die needlessly while waiting for Big Pharma to get its act together to do in decades what Jim had done in weeks !

Life is much stranger than fiction.